The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended entrectinib for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, as well as for the treatment of adult patients with ROS1-positive, advanced non–small cell lung cancer not previously treated with ROS1 inhibitors.
Levi Garraway, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended entrectinib (Rozlytrek) for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, as well as for the treatment of adult patients with ROS1-positive, advanced non—small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.1
The CHMP based its recommendation on data from the phase 2 STARTRK-2, phase 1 STARTRK-1, phase 1 ALKA-372-001, and phase 1/1b STARTRK-NG trials. The European Commission will now review the CHMP recommendation and make a final decision in the next few months.
“Once approved, Rozlytrek could become Roche’s first tumor-agnostic therapy in Europe,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche stated in a press release. “This milestone therefore represents additional progress in personalized healthcare. Based on genomic testing, Rozlytrek provides an effective first-line treatment for many people whose cancers harbor NTRK or ROS1 gene fusions, including tumors that have progressed to the brain.”
The FDA approved entrectinib for these indications in August 2019 based on findings from an integrated analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 trials, which demonstrated a 57% overall response rate (ORR) in patients with NTRK fusion—positive solid tumors.2 The decision was also based on data from the STARTRK-NG study. The trials enrolled patients across 15 countries and 150 clinical trial sites.
The integrated analysis included data for 53 patients with ROS1-activating gene fusions and 54 patients with locally advanced or metastatic NTRK fusion—positive solid tumors from STARTRK-2, STARTRK-1, and ALKA-372-001 trials—comprising 10 tumor types with more than 19 histopathologies. Tumor types included breast cancer, cholangiocarcinoma, colorectal cancer, gynecological cancer, neuroendocrine tumors, NSCLC, salivary gland cancer, pancreatic cancer, sarcoma and thyroid cancer.
The 54 patients with NTRK fusion-positive tumors had a median age of 57.5, and women accounted for almost 60% of the patients. More than 40% of the patients had received ≥2 or more prior lines of therapy, and 37% had untreated cancers.
In the international, multicenter, open-label, ongoing phase 2 STARTRK-2 basket trial (NCT02568267), investigators are enrolling 300 patients with solid tumors that harbored an NTRK1-/2-/3-, ROS1- or ALK-positive gene fusion. The primary endpoint is ORR; secondary endpoints include duration of response (DOR), time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), central nervous system (CNS) PFS, and overall survival (OS).
The multicenter, open-label, dose-escalation, phase 1 STARTRK-1 trial (NCT02097810) evaluated a daily continuous dosing schedule of entrectinib in patients with solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions in the United States and South Korea. Investigators evaluated the safety and tolerability of entrectinib via a standard dose escalation and determined the recommended phase 2 dose of entrectinib to be 400 mg/m2 daily.
Third, the multicenter, open-label, dose-escalation, phase 1 ALKA-372-001 study (NCT02097810) evaluated an intermittent and continuous entrectinib dosing schedule in patients in Italy with advanced or metastatic solid tumors with TRKA/B/C, ROS1 or ALK gene fusions.
Finally, the phase 1/1b dose-escalation and dose-expansion STARTRK-NG study is investigating the safety and efficacy of entrectinib in pediatric and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without TRK, ROS1 or ALK fusions.
Results from the integrated analysis showed that the responses were observed across 10 solid tumor types, including in patients with and without CNS metastases at baseline. Moreover, the intracranial ORR (IC ORR) was 54.5%, with more than one-quarter of these patients achieving a complete response. The median DOR ranged from 2.8 to 26.0+ months.
The responses were consistent in several subgroup analyses, including CNS metastases at baseline (50.0%, n=12) versus none (59.5%, n=42); and NTRK gene type—NTRK1 (59.1%, n=22), NTRK2 (0%, n=1), and NTRK3 (58.1%, n=31). Furthermore, the median PFS was 11.2 months and the median OS was 20.9 months.
Additionally, the pooled findings from STARTRK-2, STARTRK-1, and ALKA-372-001, showed that entrectinib demonstrated a 78% ORR and a median DOR of 24.6 months in patients locally advanced or metastatic ROS1-positive NSCLC; the IC ORR was 55.0%. Moreover, the DOR ranged from 1.8 to 36.8+ months.
Regarding safety, adverse events (AEs) with entrectinib was consistent with that seen in prior studies. The most commonly reported AEs included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.
Results of the STARTRK-NG trial were presented at the 2018 ASCO Annual Meeting, demonstrating that 3 pediatric and young adult patients with advanced, previously treated CNS tumors with targeted gene fusions—DCTN1-ALK inflammatory myofibroblastic tumors (IMT), TFG-ROS1 IMT, and EML4-NTRK3 infantile fibrosarcoma—responded to entrectinib.3 Based on these data, investigators identified the recommended phase 2 dose for children, adolescents, and young adults with solid tumors at 550 mg/m2 of daily entrectinib.
The NTRK fusion indication would specifically be for patients who have disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity; and who have not received a prior NTRK inhibitor and have no satisfactory treatment options.